In the United States, recent estimates suggest that more than 750,000 patients per year are at high risk for developing septic shock with mortality rates reaching 60%. Thus there are huge societal and financial costs associated with this syndrome. Because of its high incidence and poor prognosis, we propose basic research focused on the innate immune system and its interface with the adaptive immune system. We acknowledge that the pathophysiology of severe sepsis/shock is exceedingly complex. There is little doubt, however, that there is often a progression from infection --) normal systemic response (sepsis) --) severe sepsis --) shock and that the primary event in this sequence is infection. There is also important evidence that the intensity of the inflammatory process at the site(s) of infection determine the severity of the systemic reaction to infection, and thus the occurrence of severe sepsis and shock. It is our contention that the only means to approach such a complex system is to use appropriate cellular and animal model systems and apply the principles of systems biology in their analysis. To accomplish this we have brought together investigators with many different scientific backgrounds and specialties that include cutting-edge bioinformatics, genomic and proteomic analyses, cell biology, studies of innate and adaptive immunity, biological network modeling etc. Most importantly, we have combined experts in the field of innate immunity with "new scientific blood" such as experts in the fields of genomics, proteomics and bioinformatics. It is our contention that in the context of this GLUE GRANT this combination of investigators will, in our highly interactive and interdependent setting, substantially expand the formulation of new concepts for this field. This effort will form the basis for a great many hypothesis-driven studies by the scientific community at-large, both basic and clinical. These studies will also identify potential new drug targets that could lead to new therapies for sepsis and shock. This would directly impact the clinical outcome of these critically ill patients.